Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination.

Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.

Obesity variants in the GIPR gene do not associate with risk of fracture or bone mineral density.

OBJECTIVE: The objective of this study was to investigate the risk of fracture and bone mineral density (BMD) of sequence variants in GIPR that reduce the activity of the GIPR receptor and have been associated with reduced body mass index (BMI). METHODS: We analysed the association of three missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and two rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss of function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analysed associations with fractures at different skeletal sites in the general population; any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically non-vertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy X-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD). RESULTS: None of the three missense variants in GIPR associated significantly with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR were not associated with fractures or with BMD measured with clinically validated DXA, but associated with eBMD. CONCLUSION: Missense variants in GIPR, or burden of LoF variants in the gene, do not associate with risk of fractures or with lower BMD.

An atlas of genetic determinants of forearm fracture.

Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.

suPARnostic: an advanced predictive tool for detecting recurrence in renal cell carcinoma.

BACKGROUND: Plasma soluble urokinase-type Plasminogen Activator Receptor (suPAR) predicts disease aggressiveness in renal cell carcinoma (ccRCC), but its prognostic accuracy has not been investigated. To investigate the prognostic accuracy of preoperative plasma suPAR in patients who received curative treatment for initially localized ccRCC. METHODS: We retrospectively analyzed plasma samples stored in the Danish National Biobank between 2010 and 2015 from 235 patients with ccRCC at any stage. Relationships with outcome analyzed using univariate and multiple logistic Cox regression analysis. RESULTS: There were 235 patients with ccRCC. The median follow-up period was 7.7 years. In univariate analysis suPAR ≥ 6 ng/mL was significantly associated with overall survival (OS) and recurrence-free survival (RFS). Patients with elevated suPAR were more likely to recur, with a Hazard Ratio (HR) of 2.3 for RFS. In multiple logistic regression, suPAR ≥ 6 ng/mL remained a negative predictor of OS and RFS. Limitations include retrospective study design, wide confidence intervals, and tumor subtype heterogeneity bias. CONCLUSIONS: ccRCC patients with high plasma suPAR concentrations are at an elevated risk of disease recurrence and see lower OS. suPAR is a promising surveillance tool to more precisely follow up with ccRCC patients and detect future recurrences. In this study, we showed that new type of liquid marker in blood plasma, called suPAR, is associated to a higher risk of kidney cancer recurrence when elevated above 6ng/mL. We also showed suPAR to independently be able to predict patients overall and recurrence free survival in patient with any stage of kidney cancer.

Circulating microRNAs for Early Diagnosis of Ovarian Cancer: A Systematic Review and Meta-Analysis.

In this study, we conducted a systematic review and meta-analysis to summarize and evaluate the global research potential of different circulating miRNAs as an early diagnostic biomarker for OC. A systematic literature search for relevant studies was conducted in June 2020 and followed up in November 2021. The search was conducted in English databases (PubMed, ScienceDirect). The primary search resulted in a total of 1887 articles, which were screened according to the prior established inclusion and exclusion criteria. We identified 44 relevant studies, of which 22 were eligible for the quantitative meta-analysis. Statistical analysis was performed using the Meta-package in Rstudio. Standardized mean differences (SMD) of relative levels between control subjects and OC patients were used to evaluate the differential expression. All studies were quality evaluated using a Newcastle-Ottawa Scale. Based on the meta-analysis, nine miRNAs were identified as dysregulated in OC patients compared to controls. Nine were upregulated in OC patients compared to controls (miR-21, -125, -141, -145, -205, -328, -200a, -200b, -200c). Furthermore, miR-26, -93, -106 and -200a were analyzed, but did not present an overall significant difference between OC patients and controls. These observations should be considered when performing future studies of circulating miRNAs in relation to OC: sufficient size of clinical cohorts, development of consensus guidelines for circulating miRNA measurements, and coverage of previously reported miRNAs.

Deep integrative models for large-scale human genomics.

Polygenic risk scores (PRSs) are expected to play a critical role in precision medicine. Currently, PRS predictors are generally based on linear models using summary statistics, and more recently individual-level data. However, these predictors mainly capture additive relationships and are limited in data modalities they can use. We developed a deep learning framework (EIR) for PRS prediction which includes a model, genome-local-net (GLN), specifically designed for large-scale genomics data. The framework supports multi-task learning, automatic integration of other clinical and biochemical data, and model explainability. When applied to individual-level data from the UK Biobank, the GLN model demonstrated a competitive performance compared to established neural network architectures, particularly for certain traits, showcasing its potential in modeling complex genetic relationships. Furthermore, the GLN model outperformed linear PRS methods for Type 1 Diabetes, likely due to modeling non-additive genetic effects and epistasis. This was supported by our identification of widespread non-additive genetic effects and epistasis in the context of T1D. Finally, we constructed PRS models that integrated genotype, blood, urine, and anthropometric data and found that this improved performance for 93% of the 290 diseases and disorders considered. EIR is available at https://github.com/arnor-sigurdsson/EIR.

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Seroprevalence and infection fatality rate of the SARS-CoV-2 Omicron variant in Denmark: A nationwide serosurveillance study.

Background: Introduction of the Omicron variant caused a steep rise in SARS-CoV-2 infections despite high vaccination coverage in the Danish population. We used blood donor serosurveillance to estimate the percentage of recently infected residents in the similarly aged background population with no known comorbidity. Methods: To detect SARS-CoV-2 antibodies induced due to recent infection, and not vaccination, we assessed anti-nucleocapsid (anti-N) immunoglobulin G (IgG) in blood donor samples. Individual level data on SARS-CoV-2 RT-PCR results and vaccination status were available. Anti-N IgG was measured fortnightly from January 18 to April 3, 2022. Samples from November 2021 were analysed to assess seroprevalence before introduction of the Omicron variant in Denmark. Findings: A total of 43 088 donations from 35 309 Danish blood donors aged 17-72 years were screened. In November 2021, 1·2% (103/8 701) of donors had detectable anti-N IgG antibodies. Adjusting for test sensitivity (estimates ranging from 74%-81%) and November seroprevalence, we estimate that 66% (95% confidence intervals (CI): 63%-70%) of the healthy, similarly aged Danish population had been infected between November 1, 2021, and March 15, 2022. One third of infections were not captured by SARS-CoV-2 RT-PCR testing. The infection fatality rate (IFR) was 6·2 (CI: 5·1-7·5) per 100 000 infections. Interpretation: Screening for anti-N IgG and linkage to national registers allowed us to detect recent infections and accurately assess assay sensitivity in vaccinated or previously infected individuals during the Omicron outbreak. The IFR was lower than during previous waves. Funding: The Danish Ministry of Health.

IL-6 Autoantibodies Predict Lower Platelet Counts and Altered Plasma Cytokine Profiles in Healthy Blood Donors: Results From the Danish Blood Donor Study.

Cytokine-specific autoantibodies (c-aAb) represent a novel type of immune dysfunction. Though they have been detected in both patient cohorts and healthy individuals, and have immunomodulatory properties, the full extent of their influence remains unknown. Based on the critical role of several cytokines in thrombopoiesis, we investigated if there is an association between c-aAb and platelet variables in healthy individuals, with a specific focus on c-aAb against a known thrombopoietic cytokine, IL-6. Using platelet count and mean platelet volume in 3,569 healthy participants of the Danish Blood Donor Study as dependent variables, we performed a series of multivariate regression analyses using five cytokine autoantibodies, including IL-6 c-aAb, as independent variables. In men, high titers of IL-6 c-aAb were negatively associated with platelet counts (ß = -24 *109/l (95% confidence interval -43 to -6), p = 0.008) and positively associated with mean platelet volume (ß = 0.4 fL (95% confidence interval 0.0-0.7) p = 0.043). These associations were exacerbated when adjusting for undetectable C-reactive protein levels, which we used as a proxy for c-aAb mediated IL-6 inhibition in vivo. Furthermore, in a smaller subgroup, individuals with high vs. low titer IL-6 c-aAb had different profiles of plasma IL-6, IL-10, TNFα and TPO, further suggesting a functional inhibition of IL-6 by high titers of circulating IL-6 c-aAb. We therefore speculate that in addition to their immunomodulatory potential IL-6 c-aAb may interfere with thrombopoiesis - directly or indirectly - under normal physiological conditions. This study is the first to suggest an influence of c-aAb on platelets in healthy individuals, beyond their apparent effects on immune competence.

Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

INTRODUCTION: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants. MATERIALS AND METHODS: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex. RESULTS: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption. DISCUSSION: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.

No evidence of transfusion transmitted sporadic Creutzfeldt-Jakob disease: results from a bi-national cohort study.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is an uncommon, invariably fatal, neurodegenerative disorder that presents as progressive dementia with concurrent motor symptoms and myoclonia. The pathophysiology involves prion protein misfolding and spreading in a self-catalyzed manner. It has been shown to be transmissible through tissue transplants. Variant CJD (vCJD), a subtype of the disease is also transmissible through transfusion of blood products. This study aims to corroborate the scarce data that suggest that sporadic CJD (sCJD) is not transmitted via blood transfusion. METHODS AND STUDY DESIGN: A retrospective cohort study was performed, using data from the bi-national Scandinavian Donations and Transfusions (SCANDAT2) database containing data on blood donors, donations, transfusions, and transfused patients in Sweden and Denmark since 1968 and 1982, respectively. Mortality and medical data were collected from nationwide health care and population registries. Donors with subsequent CJD were identified, as well as recipients of blood products from these donors. A second analysis was performed, screening for clustering of CJD cases from donors without a CJD diagnosis. RESULTS: We identified 39 donors with a subsequent diagnosis of sCJD. No cases of CJD occurred among the 883 recipients of blood products from these donors. A total of 89 CJD cases were identified among recipients of transfusions. No clustering of cases from the same donor occurred. DISCUSSION: Using data from a large, bi-national database of transfused patients, we find no evidence of sCJD transmission. Our data adds to the growing body of evidence indicating that sCJD is not transfusion transmitted.